This invention relates to an intravaginal ring herein sometimes referred to as an IVR containing contraceptive steroids, a method of manufacturing the intravaginal rings and a method of contraceptive treatment in mammals using this intravaginal ring.
A variety of chemical and mechanical methods for controlling fertility and for preventing pregnancy are known. Approaches such as sterilization, the use of condoms, IUDs, spermicidal creams and jellies, foam tablets, and oral pills are currently available as a prevention against pregnancy. These methods, though effective to a variable extent, also have limitations. Most of the devices require constant motivation on the part of the user and some approaches such as sterilization and IUDs require specialized medical attention. The oral pill is a popular method of contraception but the oral contraceptives have many undesirable side effects and require the daily ingestion of a tablet. The use of the IVR as a means of administering effective contraceptive steroids through a vaginal route was seen as a means of overcoming some of these drawbacks.
Intravaginal rings are annularly shaped articles which can be introduced into the vagina in a simple manner without medical assistance. The IVR fits between the rear wall of the vagina and the upper edge of the pubic bone. The IVR device is primarily useful for the inhibition of fertility, that is contraceptive purposes, but is also used to treat and medicate other conditions. IVRs are designed so that they can be retained in the vagina for a period up to about one year. In routine contraceptive use, the ring is inserted in the vagina for 3 weeks, removed for one week and reinserted on a schedule of three weeks in, one week out.
Depending on the anatomy of the patient, the IVR may vary in size, for example from 45 mm to 65 mm in outer diameter. IVRs contain medication, for example, effective contraceptive steroids which diffuse through the IVR and are absorbed by the surrounding body fluid through the vaginal mucosa. The IVR exerts its medicative effect as long as the IVR is retained within the body and the supply of the medication is sufficient.
The concept of using intravaginal rings as a means of administering effective contraceptive steroids by absorption through the vaginal mucosa for contraceptive purposes was tested by Mishell and associates in 1970, Mishell, D. R. Jr., et al. Am. J. Obstet. Gynecol. 107:100, 1970.
The results of these tests indicated that IVRs containing an effective amount of contraceptive steroids offer a reliable and acceptable method of contraception. During the years from 1970 to 1975 a series of clinical studies with a variety of steroids and IVR designs were undertaken to develop a practical IVR. As a result of that work, IVRs containing effective contraceptive steroids have now been developed with several different designs and made from a wide variety of materials. A variety of inert elastomers or combinations of elastomers are suitable for making IVRs; for example, organopolysiloxanes of the linear type converted to rubber by various catalysts such as stannous octoates, platinum salts and peroxides and/or by heat provide a compatible nontoxic matrix for IVRs. Useful materials for making IVRs include, for example, conventional silicone rubber, Silastic 382.sup.1, polyurethane, latex rubber, polyamides, polyesters, polytetrafluoroethylene, polyethylene vinyl acetate and nylon. FNT .sup.1 Silastic is a trademark of Dow Corning Corporation for a silicone polymer.
There are four basic IVR designs, denominated for this description as the homogeneous IVR, the Schering IVR, the Roseman IVR, and the shell IVR. For further details on IVR designs, see New Delivery Systems for D-Norgestrel, Weiner et al., Acta Obstet Gynecol. Scand, Suppl. 54, 1977 p. 35, U.S. Pat. No. 3,920,805 to Roseman and U.S. Pat. No. 4,012,496 to Schopflen.
In the homogeneous IVR, the contraceptive steroid is dispersed throughout an inert elastomer matrix as described in U.S. Pat. No. 3,545,439 to Duncan or in Victor et al., Contraception 12:261, 1975; see FIG. 3.
The Schering IVR consists of an inert elastomer ring encircled by a second ring of inert elastomer impregnated with a contraceptive steroid. For a discussion of this type of IVR see U.S. Pat. No. 4,012,496 to Schoepflin et al.
In the Roseman IVR a thin layer of an inert elastomer containing a contraceptive steroid is molded onto a central inert core of elastomer; see FIG. 5.
In the shell IVR, of which the present invention is an improvement, a thin medicated layer of an inert elastomer containing a contraceptive steroid surrounds a central inert core of synthetic elastomer and the medicated layer is surrounded by an outer layer of inert elastomer of variable thickness. The thickness of the outer layer is varied to control the release rate of the steroid; see FIG. 4. Clinical research with the shell IVR has been described in Mishell D. R., Jr. et al. Clinical Performance and Endocrine Profiles with Contraceptive Vaginal Rings Containing a Combination of Estradiol and d-Norgestrel, Am. J. Obstet Gynecol, 130:55 (1978); see also Weiner supra. The clinical acceptance of the shell design IVR thus far has been favorable.
The release of the contraceptive steroids from any of the four IVR designs is governed by Fick's law. According to Fick's law, as applied to systems with suspended solutes, the mass (M) transferred across a boundary per unit time (t) will be a function of the concentration of the mass at saturation (C.sub.s) and the diffusion (D.sub.s) and an inverse function of the distance across the boundary (h). EQU (dM/dt)=(D.sub.s C.sub.s /h)
When a drug such as a contraceptive steroid is suspended in a stationary matrix as in the IVR, h is the distance from the surface of the matrix to the plane in the matrix where the drug is located. When diffusion of the drug from the matrix occurs, the drug supply nearest the surface of the matrix will diffuse first and the distance h will increase as diffusion of the drug continues. This increase in the distance h from the surface of the matrix to the plane where the drug is located increases the time required for the drug to reach the surface and thereby decreases the amount of drug being transferred to the surface of the matrix per unit time. Based on Fick's law, it can be demonstrated.sup.2 that the amount of drug transferred to the surface of the matrix will be a linear function of the square root of time. FNT .sup.2 Flynn, G. L., Yalkowsky, S. H. and Roseman, T. J.: Mass transport phenomenona and models: Theoretical concepts. J. Pharm. Chem. 63 479-510, 1974.
In applying Fick's law to the diffusion of contraceptive steroids from various IVR designs, several factors must be considered. If the reservoir of contraceptive steroids in an IVR is dispensed uniformly throughout the IVR as in the homogeneous IVR, it is evident that the distance the steroid must travel to reach the surface of the IVR will increase markedly before the steroid reservoir is exhausted. The rate of release of the contraceptive steroid from the homogeneous IVR will decrease with time as the distance h increases. Similar release rate patterns are observed with the Schering IVR which in principal is similar to the homogeneous IVR.
The Roseman ring presents an improvement in IVR design in that the layer containing the steroid has been confined to a layer at the surface of the ring. However, in spite of this modification the rate of release of the steroid continues to decrease over time. The change in the distance which the steroid must travel to reach the surface of the ring still progresses from zero to a finite value and thus the relative proportional change in the rate is large and the release rate is not constant. If, however, the layer containing the contraceptive steroid is placed beneath a rate controlling layer as in the shell IVR a much more constant rate of release over time is obtained. The small proportional change in the distance the steroid must travel to reach the surface of the IVR between the time the IVR is first inserted (t=0) and the time when the supply of the contraceptive steroid is exhausted (t=x) is reflected in the more constant rate of release. These differences are illustrated in FIGS. 3, 4 and 5.
FIG. 3 shows a cross section of a homogeneous IVR, FIG. 4 shows a cross section of a shell IVR and FIG. 5 illustrates a cross section of a Roseman IVR. It can be seen from these figures that the distance h.sub.t =x is much greater for homogeneous IVRs than for the Roseman IVR and the shell IVR. For this reason both the shell IVR and the Roseman IVR are considered to be more useful designs for controlling release rates of steroids than the homogeneous IVR. By comparing FIGS. 4 and 5 it can be seen that the relative changes in distance between h.sub.t =0 and h.sub.t =x will be less for the shell design IVR than for the Roseman IVR since in the shell IVR h.sub.t =0 has a finite value. The relative change from h.sub.t =0 to h.sub.t =x and the corresponding change in the release of medication observed with the Roseman IVR interfers with attempts to supply constant daily doses of contraceptive steroids to the patient, which is an important consideration in administering these steroids.
An additional drawback of previously developed IVRs is that with the exception of Duncan's IVR disclosed in U.S. Pat. No. 3,545,439, IVRs usually do not contain estrogen and contain only a progestationally active steroid alone and not in combination with estrogen. The use of progestionally active steroids alone in IVRs not in combination with estrogen leads to undesirable irregular breakthrough bleeding or spotting. Breakthrough bleeding is bleeding which occurs during the 21 day period when the IVR is in place. In unmedicated women, the intervals of about three weeks between menstrual bleeding events is usually free from bleeding and such bleeding is undesirable. Spotting is distinguished from breakthrough bleeding only in that a lesser amount of blood is voided. When the amount of blood is great enough that the woman feels that she needs the protection of a sanitary pad or tampon, the occurence is designated as "bleeding". When the amount of blood is less than this, it is designated as "spotting".
Estrogens have been known to improve bleeding and spotting control when administered orally in combination with other steroids in the oral contraceptive pill; however, estrogens are also known to cause a variety of undesirable metabolic changes especially in the liver. These changes are believed to increase the incidence of thromboembolisms, strokes and cardiac infarctions and for this reason estrogens have not been extensively used in IVRs to control breakthrough bleeding.
An improved shell IVR has now been found. The improvement comprises in combination, an inert elastomer core, a medicated layer attached to and encircling the core and an outer inert elastomer layer. The outer inert elastomer layer has a thickness of about 0.1 to 0.6 mm and the medicated layer has a thickness of not more than twice the thickness of the outer layer and contains an inert elastomer and a combination of estradiol-17.beta. with a progestogen selected from the group consisting of levonorgestrel, d,1-norgestrel and norethindrone.
The IVR has an inert core with an overall diameter of from about 45 mm to 65 mm preferably from 48 mm to 60 mm. The cross sectional diameter of the inert core is from about 5 mm to 10 mm, preferably from 7-9 mm. The medicated layer may be from about 0.05 to 1 mm thick with the provision that it is not more than twice the thickness of the outer layer, preferably 0.1 to 0.2 mm. The outer layer may be from about 0.1 to 0.6 mm thick preferably 0.2 mm. The thickness of the outer layer affects the distance the steroid must travel to reach the subjects system and thereby is used to control the release rate of the steroid.
The inert elastomer core can be constructed from the following classes of elastomer;
1. Thermosetting organopolysiloxanes to be vulcanized with peroxide curing catalysts, e.g. benzoyl peroxide or di-p-chlorobenzoyl peroxide at temperatures of about 200.degree. C. and requiring a heat aftertreatment, e.g. those described in U.S. Pat. No. 2,541,137; 2,723,966; 2,863,846; 2,890,188 and 3,022,951. PA1 3. Single-component silicone rubber compositions which are cured at room temperature under atmospheric humidity without any further additives. These single component compositions contain primarily organopolysiloxanes with two terminal-positioned hydrolyzable acyloxy groups, e.g. acetoxy; the acyloxy groups are hydrolyzed under atmospheric humidity to form trifunctional siloxane units which crosslink the polymer into a cured elastomer. Such organopolysiloxanes are described, e.g., in U.S. Pat. Nos. 2,927,907 and 3,035,016 and in British Pat. Nos. 798,669 and 804,199. PA1 4. Two-component dimethylpolysiloxane compositions, platinum-catalyzed at room temperature or under slightly elevated temperature and capable of addition cross-linking. The medicated layer can be constructed from an elastomer selected from classes 2 and 3 above and the outer layer can be constructed from an elastomer selected from classes 1 to 4 above, provided the elastomers in class 1 are cured before coming in contact with the medicated layer. The preferred elastomers for use in the core, medicated layer and the outer layer are polydimethylsiloxanes. PA1 (a) forming an annular core ring of suitable inert elastomer by injecting the unvulcanized elastomer into a mold and allowing it to cure; PA1 (b) removing the ring and dipping it in an mixture of an inert volatile solvent containing a mixture of contraceptive steroid and an inert unvulcanized elastomer adhesive; PA1 (c) removing the ring from the mixture and allowing the solvent to evaporate; PA1 (d) repeating steps b and c until a medicated layer of the desired thickness is obtained; PA1 (e) dipping the ring from step d into a mixture of an inert unvulcanized elastomer in an inert volatile solvent and allowing the solvent to evaporate to form an outer layer; and PA1 (f) repeating step e until an outer layer of the desired thickness is obtained. PA1 (a) forming a core rod of suitable inert elastomer by injecting the unvulcanized elastomer into a mold, and allowing it to cure; PA1 (b) removing the resulting core rod and cutting it into lengths about 15.5 cm; PA1 (c) bringing the rod to a constant weight by either heating at about 110.degree. C. or allowing the rod to stand at room temperature. PA1 (d) pulling it through a coating solution containing a mixture of an elastomer and a mixture of estradiol and a progestogen; PA1 (e) dipping the coated rod in a catalyst solution such as toluene or another solvent which will not substantially dissolve the steroid and allowing the coating to polymerize; PA1 (f) swelling a piece of tubing in a volatile organic solvent, and sliding it over the coated rod from step e and allowing the solvent to evaporate; PA1 (g) trimming the excess tubing from the ends of the rod and applying a medical grade adhesive to the ends of the rod and to the surface of the rod close to the end; PA1 (h) placing a second piece of swollen tubing of about 4 cm in length over both ends of the rod to form a ring and holding the ends of the rod together for 24 hours until the adhesive has cured. PA1 (a) forming an annular core ring of suitable inert elastomer by injecting the unvulcanized elastomer into a mold and allowing it to cure, removing the circular ring from the mold and cutting it open; PA1 (b) bringing the open ring to a constant weight by either heating at about 110.degree. C. or allowing the rod to stand at room temperature and pulling it through a coating solution containing an unvulcanized elastomer and mixture of estradiol and a progestogen; PA1 (c) dipping the coated open ring in a catalyst solution in a solvent such as toluene which will not substantially dissolve the steriod and allowing the coating to polymerize; PA1 (d) swelling a piece of tubing in a volatile organic solvent, fitting it over the open ring from step c and allowing the solvent to evaporate; PA1 (e) trimming the excess tubing from the ends of the open ring and applying a medical grade adhesive to the ends of the open ring and to about 1 cm of the surface of the open ring close to the end; PA1 (f) placing a second piece of swollen tubing of about 4 cm in length over both ends of the open ring to reform the ring, and PA1 (g) holding the ends of the open ring together for 1-2 minutes and allowing the adhesive to cure for about 24 hours.
2. Hydroxyl-terminated organopolysiloxanes of the RTV (room temperature vulcanizing) type which harden to elastomers at room temperature after the addition of cross-linking agents in the presence of curing catalysts and under the atmospheric humidity. Typical curing catalysts are metallic salts of carboxylic acids, preferably tin salts, e.g. tin (II) octoate and tin (II)-2-ethylhexanoate.
It is recognized, of course that other elastomers may be used in preparing the core.
The medicated layer contains an inert elastomer and a combination of estradiol-17.beta. with progestogen selected from the group consisting of levonorgestrel, d-1-norestrel and norethindrone, preferably levonorgestrel. The amount of steroid used in the medicated layer is adjusted according to the expected total time of use of the IVR. It is necessary to add sufficient amounts of the steroids to prevent pregnancy throughout the period of expected use. A 30%-50% excess over average requirements is also provided to allow for variations in the absorbtion rate in different patients.
The amount of contraceptive steroids which can be used in the medicated layer is limited by the cost of the steroids and the amount of steroid that can be included in the medicated layer without weakening the structure or exceeding the dimensions of the ring. An IVR designed for one month's use requires about 3 to 10 mg of estradiol and about 4-20 mg of levonorgestrel to release an amount of the steroid sufficient to prevent pregnancy. If d,1-norgestrel is used in the IVR about 8-40 mg would be required. An IVR designed for 6 month's use requires about 20-120 mg of levonorgestrel preferably about 70 mg and about 15-50 mg of estradiol preferably about 35 mg. If d,1-norgestrel is used about 40-240 mg would be required. If norethindrone is used in a six month IVR about 60-200 mg preferably 120 mg would be required. An IVR designed for one year's use would contain about 30-100 mg of estradiol and about 40-240 mg of levonorgestrel. If d,1-norgestrel is used in the IVR, about 80-480 mg are required for one year's use.
The shell IVR of the present invention has a uniform rate of release of the steroid to the subject's system. Unlike the homogeneous IVR or the Roseman IVR, the shell IVR of this invention has a relatively uniform release rate over a 3 month to one year period.
It has further been found that the IVR of this invention can be used in a method of contraceptive treatment in humans with a reduction in breakthrough bleeding and with minimal effects on liver metabolism.
Studies conducted by Mishell et al. Am. J. Obstet. Gynecol. 130, No. 1 Jan. 1, 1978 conclude that women using IVRs of this invention containing both estradiol and levonorgestrel have significantly better bleeding patterns than those using IVRs of the same design but containing levonorgestrel alone and that they produce a minimal effect on liver metabolism.
Many of the undesirable side effects associated with the oral administration of estrogen are thought to be associated with changes in women's metabolism. Such metabolic changes result in several measurable changes in the women's system. Among the changes thought to be important are increased circulating levels of triglycerides, and angiotensinogen, increased levels of clotting factors I, II, VII, IX, X and XIII and decreased levels of antithrombin III. Other changes that also occur but are not clearly implicated in serious health effects include increase in circulating corticosteroid binding globulin, sex hormone binding globulin, certain transaminases, and ceruloplasmin.
In contrast to the changes observed when estrogens are administered orally, there have not been significant increases in circulating triglycerides, corticosteroid binding globulin or angiotensinogen in women using IVRs containing combinations of levonorgestrel and estradiol.
It is believed that there are two possible reasons that the effect on liver metabolism observed with orally administered combinations of progestins and estrogens are not observed with the IVR of this invention. First, the natural steroid, estradiol is used in the shell IVR of this invention instead of the synthetic steroids ethinyl estradiol or mestranol that are used in oral contraceptives. A second reason for fewer metabolic affects when contraceptive steroids are administered vaginally instead of orally may be that with the vaginal route of administration the steroids are diluted by passage through a major portion of the circulation system before they reach the liver. When they are administered orally, portal circulation carries material absorbed through the intestinal wall directly to the liver.
It has further been found that the shell IVR of the present invention can be manufactured by several different methods. One method consists of:
Suitable inert elastomers for use in this process are listed above. Suitable inert volatile solvents without limitation are toluene, hexane, benzene, xylene, and other organic solvents with low solubility for the steroids. The mold is preferably made of brass.
A medicated layer of from 0.05 mm to 1 mm can be used provided the medicated layer is not more than twice the thickness of the outer layer. Preferably the medicated layer is 0.1-0.2 mm thick.
The outer layer is of variable thickness from 0.1 mm to 0.6 mm, preferably 0.2 mm. The outer layer controls the release rate of the steroid from the IVR and can be varied accordingly.
An alternative method of making shell IVRs of this invention consists of:
Another alternative and preferred method of manufacturing shell IVRs of this invention consists of:
Suitable solvents for use in swelling the tubing are heptane, hexane, or other non polar solvents in which the steroid is only slightly soluble.